Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands

ABSTRACT

Disclosed are compounds of compounds of the formula: ##STR1## or the pharmaceutically acceptable nontoxic salts thereof wherein: X is oxygen, H 2  or sulfur 
     Y is hydrogen, or optionally substituted alkyl, alkenyl, (substituted)arylalkyl, aryl or heteroaryl, or a carbonyl group substituted with alkyl, cycloalkyl, aryl, or amino groups; 
     W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group is optionally substituted with up to two groups; or 
     W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionally substituted; and 
     Z 1 , Z 2 , Z 3 , and Z 4  independently represent nitrogen or C-R 1  where 
     R 1  is hydrogen, halogen, hydroxy, amino, or phenyl or pyridyl optionally mono- or independently disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, 
     which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel imidazo 1,5-c!quinazolines whichselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 40 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings; these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Phaimakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 mM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepam-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. This data was interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 274: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, the triazolo-pyridazineinteracted with benzodiazepine sites with a Hill coefficient of 1(Squires et al., 1979, Pharma. Biochem. Behav. 10: 825-30, Klepner etal. 1979, Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiplebenzodiazepine receptors were predicted in the cortex, hippocampus,striatum, but not in the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther, 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into ∝, β, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous. A biochemical test forthe pharmacological and behavioral properties of compounds that interactwith the benzodiazepine receptor continues to emphasize the interactionwith the GABAergic system. In contrast to the benzodiazepines, whichshow an increase in their affinity due to GABA (Tallman et al., 1978,Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81),compounds with antagonist properties show little GABA shift (i.e.,change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature294: 763-65), and the inverse agonists actually show a decrease inaffinity due to GABA (Braestrup & Nielson 1981, Nature 294: 472-474).Thus, the GABA shift predicts generally the expected behavioralproperties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example, PCT publications WO 92/22552 and WO 9317025 aswell as several other references disclose compounds useful in treatingdisorders of the central nervous system.

WO 92/22552 teaches compounds of the Formula A: ##STR2## Wherein R₃ =H,alkyl, cycloalkyl, hydroxy, alkoxy, amino, amino-carbonyl,alkoxycarbonyl, heterocyclic ring or aryl etc;

R₄ =H₂ or H and OH or H and heterocyclic ring with R₅ ;

R₅ =carbonyl, alkanoyl, aminocarbonyl, hydroxyaminocarbonyl or thienyletc;

W₆ =N or --CR₆ ;

R₆ =H, halogen, --CN, --NO₂, --CF3, --OCF3, --CH₂ CH₂ OH, cycloalkyl,alkoxycarbonyl, alkyl, aminocarbonyl, hydroxyaminocarbonyl or thienyletc;

W₇ =N or --CR₇, R₇ =R₆ ;

W₈ =N or --CR₈, R₈ =R₆ ; and

W₉ =N or --CR₉, R₉ =R₆.

WO 9317025 discloses compounds of Formula B: ##STR3## Wherein R₃ is##STR4## --Aryl=aryl or heteroaryl with various substituents; R₅ =alkyl,cycloalkyl, alkyl-cycloalkyl, alkenyl, (CH₂)_(n) --Aryl, (CH₂)_(m) oralkoxy; n=0-4; m=2-4;

R₆ and R₇ =H, F, Br, Cl, I, CN, NO₂, alkoxy, alkoxycarbonyl oraminocarbonyl etc.;

R₈ =O, S, --NH, --NCH₃, --N-alkyl-cycloalkyl or --NCHO;

R₉ =H, alkyl, phenyl; and

R₁₁ =H, alkyl, cycloalkyl, alkyl-cycloalkyl or (CH2)n-Aryl.

Several references teach compounds of Formula C: ##STR5##

For example, U.S. Pat. No. 4,999,353 and EP 368,652 disclose4-oxo-imidazo 1,5-a!quinoxalines useful as anxiolytics and hypnoticswith an oxadiazole at position 3 and tert-butyl at position 5.

European Patent 320,136 discloses 4-oxoimidazo 1,5-a!-quinoxalinecompounds useful as anxiolytic and hypnotic agents, containingoxadiazole or ester substituents at the 3-position and hydrogen orhalogen substituents at the 6-position. The ring atom at position 6 maybe carbon or nitrogen.

European Patent 344,943 discloses a group of imidazo 1,5-a! quinoxalinecompounds, useful as anxiolytic and anticonvulsant agents, having amethyl with different substituents at the 5-position.

U.S. Pat. No. 5,116,841 and PCT publication WO 91/07407 disclose4-oxoimidazo 1,5-a!quinoxalines useful as anxiolytics and hypnotics withisoxazoles at position 3.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I: ##STR6## or thepharmaceutically acceptable nontoxic salts thereof wherein: X is oxygen,H₂ or sulfur

Y is hydrogen, alkyl, alkenyl, (substituted)arylalkyl, alkoxycarbonyl,acyl, aroyl, alkoxyalkyl, alkoxy, alkylamino-carbonyl,cycloalkylaminocarbonyl, aryl or heteroaryl each of which is optionallysubstituted with halogen, lower alkyl, amino lower alkyl, or loweralkoxy;

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl, and

Z₁, Z₂, Z₃, and Z₄ independently represent nitrogen or C-R₁ where R₁ ishydrogen, halogen, hydroxy, amino, or phenyl or pyridyl optionally mono-or independently disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy.

The imidazo 1,5-c!quinazolines of the invention interact with a GABAbinding site, the benzodiazepines (BDZ) receptor. This interactionresults in the pharmacological activities of these compounds.

The compounds of the invention are highly selective agonists or inverseagonists for GABAa brain receptors or prodrugs of agonists or inverseagonists for GABAa brain receptors. These compounds are useful in thediagnosis and treatment of anxiety, sleep, and seizure disorders,overdose of benzodiazepine drugs, and enhancement of memory.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IA: ##STR7## or thepharmaceutically acceptable nontoxic salts thereof wherein: X is oxygen,H₂ or sulfur

Y' is hydrogen, alkyl, alkenyl, (substituted)arylalkyl, alkoxy,alkoxyalkyl, or aryl or heteroaryl each of which is optionallysubstituted with halogen, lower alkyl, amino lower alkyl, or loweralkoxy; or

Y' is a group of the formula: ##STR8## where R_(c) represents alkoxy,lower alkyl, aryl, heteroaryl, mono- or dialkylamino, cycloalkylamino;

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl, and

Z₁, Z₂, Z₃, and Z₄ independently represent nitrogen or C-R₁ where R₁ ishydrogen, halogen, hydroxy, amino, or phenyl or pyridyl optionally mono-or independently disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy.

Preferred compounds of formula I are those where Z₁, Z₂, Z₃, and Z₄represent C-H, Y is lower alkyl, acyl, aroyl, alkylaminocarbonyl, orcycloalkylaminocarbonyl, and W is optionally substituted aryl. Morepreferably, W represents optionally substituted phenyl.

Preferred compounds of formula IA are those where Z₁, Z₂, Z₃, and Z₄represent C-H, Y' is lower alkyl, acyl, benzoyl, dialkylaminocarbonyl,or cycloalkylaminocarbonyl, and W is optionally substituted aryl. Morepreferably, W represents optionally substituted phenyl, and Y' is--COR_(c) where --COR_(c) represents acetyl, propionyl, benzoyl,piperidinylcarbonyl, diethylaminocarbonyl, dimethylaminocarbonyl, ormorpholinylcarbonyl.

In addition, the present invention encompasses compounds of Formula II:##STR9## wherein Y is hydrogen, alkyl, alkenyl, (substituted)arylalkyl,alkoxy, alkoxyalkyl, or aryl or heteroaryl each of which is optionallysubstituted with halogen, lower alkyl, amino lower alkyl, or loweralkoxy; or

Y is a group of the formula: ##STR10## where R_(c) represents alkoxy,lower alkyl, aryl, heteroaryl, mono- or dialkylamino, cycloalkylamino;and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

Particularly preferred compounds according to Formula II are those whereW represents phenyl, or alkoxyphenyl where the phenyl group isoptionally halogenated. The most particularly preferred alkoxyphenylderivatives are the 3- and 4-alkoxyphenyl, in particular the 3- and4-methoxyphenyl derivatives of Formula II.

The present invention also encompasses compounds of Formula III:##STR11## wherein Y is hydrogen, alkyl, alkenyl, (substituted)arylalkyl,alkoxy, alkoxyalkyl, or aryl or heteroaryl each of which is optionallysubstituted with halogen, lower alkyl, amino lower alkyl, or loweralkoxy; or

Y is a group of the formula: ##STR12## where R_(c) represents alkoxy,lower alkyl, aryl, heteroaryl, mono- or dialkylamino, cycloalkylamino;and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

Particularly preferred compounds according to Formula III are thosewhere W represents phenyl, or alkoxyphenyl where the phenyl group isoptionally halogenated. The most particularly preferred alkoxyphenylderivatives are the 3- and 4-alkoxyphenyl, in particular the 3- and4-methoxyphenyl derivatives of Formula III.

In addition, the present invention encompasses compounds of Formula IV:##STR13## wherein

R_(c) represents alkoxy, lower alkyl, aryl, heteroaryl, mono- ordialkylamino, cycloalkylamino; and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

Particularly preferred compounds according to Formula IV are those whereW represents phenyl, or alkoxyphenyl where the phenyl group isoptionally halogenated. The most particularly preferred alkoxyphenylderivatives are the 3- and 4-alkoxyphenyl, in particular the 3- and4-methoxyphenyl derivatives of Formula IV.

In addition, the present invention encompasses compounds of Formula V:##STR14## wherein R_(c) represents alkoxy, lower alkyl, aryl,heteroaryl, mono- or dialkylamino, cycloalkylamino; and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

Particularly preferred compounds according to Formula V are those whereW represents phenyl, or alkoxyphenyl where the phenyl group isoptionally halogenated. The most particularly preferred alkoxyphenylderivatives are the 3- and 4-alkoxyphenyl, in particular the 3- and4-methoxyphenyl derivatives of Formula V.

In addition, the present invention encompasses compounds of Formula VI:##STR15## wherein R_(a) represents hydrogen, alkyl, alkenyl,(substituted)arylalkyl, alkoxy, alkoxyalkyl, or aryl or heteroaryl eachof which is optionally substituted with halogen, lower alkyl, aminolower alkyl, or lower alkoxy; and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

In addition, the present invention encompasses compounds of Formula VII:##STR16## wherein R_(a) represents hydrogen, alkyl, alkenyl,(substituted)arylalkyl, alkoxy, alkoxyalkyl, or aryl or heteroaryl eachof which is optionally substituted with halogen, lower alkyl, aminolower alkyl, or lower alkoxy; and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

The present invention also encompasses compounds of Formula VIII:##STR17## wherein A is oxygen, CH₂, --(CH₂)₂ -- or NH; and

W is alkyl, arylalkyl or heteroarylalkyl, where each aryl group isoptionally substituted with up to two groups independently selected fromhalogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl,mono- or dialkyl amino where each alkyl is independently lower alkyl; or

W is aryl, thienyl, pyridyl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl.

Preferred compounds according to Formula VIII are those where A isoxygen or nitrogen. Particularly preferred compounds of Formula VIII arethose where A is oxygen, and W represents phenyl, or alkoxyphenyl wherethe phenyl group is optionally halogenated. More particularly preferredcompounds of Formula VIII are those where the alkoxyphenyl group is anoptionally halogenated 3- or 4-alkoxyphenyl group, in particular anoptionally halogenated 3- or 4-methoxyphenyl group.

Other preferred compounds of Formula VIII are those where A is CH₂ or--(CH₂)₂ --, and W represents thienyl, phenyl or alkoxy phenyl where thephenyl group is optionally halogenated. More preferred compounds ofFormula VIII are those where A is methylene or ethylene and W is 2- or3- thienyl or W is 3- or 4-methoxyphenyl.

Still other particularly preferred compounds of Formula VIII are thosewhere A is CH₂, and W represents thienyl. Yet other preferred compoundsof Formula VIII are those where A is ethylene and W is alkoxyphenyl,preferably methoxyphenyl.

As noted above, the compounds of the invention are highly selectiveagonists, antagonists or inverse agonists for GABAa brain receptors orprodrugs of agonists or inverse agonists for GABAa brain receptors.These compounds are useful in the diagnosis and treatment of anxiety,sleep, and seizure disorders, overdose with benzodiazepine drugs, andenhancement of memory.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,alkanoic such as acetic, HOOC--(CH₂)_(n) --COOH where n is 0-4, and thelike. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

The following numbering system is used herein to identify positions onthe 5,6-dihydro-6-imidazo 1,5-c!quinazoline portion of the compounds ofthe invention: ##STR18##

By aryl or "Ar" is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By heteroaryl is meant 5, 6, or 7 membered aromatic ring systems havingat least one and up to four hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groupsare pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl,oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl,which can optionally be substituted with, e.g., halogen, lower alkyl,lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl,heteroaryl, and hydroxy.

Examples of various aryl and heteroaryl groups are shown in Chart D ofpublished International Application WO 93/17025.

By alkyl and lower alkyl is meant straight and branched chain alkylgroups having from 1-6 carbon atoms. Specific non-limiting examples ofalkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, neopentyl and n-pentyl.

By lower alkoxy and alkoxy is meant straight and branched chain alkoxygroups having from 1-6 carbon atoms.

By halogen is meant fluorine, chlorine, bromine and iodine.

As used herein, --COR_(c) represents a group of the formula: ##STR19##where R_(c) is defined above.

In the compounds of the invention, preferred Y groups include thefollowing: ##STR20## where A is NH, CH₂ or oxygen; E is oxygen ornitrogen; R' and R" independently represent hydrogen, halogen, hydroxy,alkyl or lower alkoxy; and R'" and R"" independently represent loweralkyl.

In the above Y groups of the invention, preferred R' and R" groups arehydrogen, halogen, or alkoxy.

More preferred Y groups of the invention include the following:##STR21## where R' and R" are as defined immediately above.

Representative examples of imidazo 1,5-c!quinazolines according to theinvention are shown in Table 1 below.

                  TABLE 1                                                         ______________________________________                                         ##STR22##                                                                     ##STR23##                                                                     ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                     ##STR29##                                                                     ##STR30##                                                                    ______________________________________                                    

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

The assay is carried out as described in Thomas and Tallman (J. Bio.Chem. 156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissueis dissected and homogenized in 25 volumes (w/v of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°C.) at 20,000×g for 20 minutes. The supernatant is decanted and thepellet is rehomogenized in the same volume of buffer and againcentrifuged at 20,000×g. The supernatant is decanted and the pellet isfrozen at -20° C. overnight. The pellet is then thawed and rehomogenizedin 25 volume (original w/v) of buffer and the procedure is carried outtwice. The pellet is finally resuspended in 50 volumes (w/v) of 0.05MTris HCl buffer (pH 7.4 at 40° C.).

Incubation contain 100 of tissue homogenate, 100 ml of radioligand (0.5nM ³ H-RO15-1788 ³ H-Flumazenil! specific activity 80 Ci/mmol), drug orblocker and buffer to a total volume of 500 ml. Incubstion are carriedfor 30 min at 4° C. then are rapidly filtered through GFB filters toseparate free and bound ligand. Filters are washed twice with fresh0.05M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total-Nonspecific. In some case, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried. Data are converted to a form for the calculation ofKi and Hill Coefficient (nH). Data for the compounds of this inventionare listed in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound Number.sup.1                                                                          Ki (nm)                                                      ______________________________________                                         1               6                                                             2               4.7                                                           3               2.7                                                          16               17                                                           18               12                                                           49               101                                                          53               7.8                                                          72               9.7                                                          76               124                                                          ______________________________________                                         .sup.1 Compound number corresponds to the compound numbers in Table 1         above as well as the compound numbers used to refer to the compounds          disclosed below in the examples.                                         

¹ Compounds number correspond to the compound numbers in Table 1 aboveas well as the compound numbers used to the compounds disclosed below inthe examples.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore nontoxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powers orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparation. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmomosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acid, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monoleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconuts oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powers and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives, Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and a hexitol,anhydrides, for example sorbitan monoleate, and condensation product ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispensing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable dilutent orsolvent, for example a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any brand fixed oil may be employed including synthetic mono-ordiglycerides. In addition fatty acid such as oleic acid find use in thepreparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperature butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may also be administered parentally in asterile medium, The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffing agents can be dissolved in the vehicle.

Dosage levels of the order of from 0.1 mg to about 140 mg per kilogramof body weight per day are useful in the treatment of the aboveindicated conditions (about 0.5 mg to about 7 g per patient per day).The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms will generally contain between from about 1mg to about 500 mg ofan active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a verity of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Schemes I and II. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention, asdemonstrated by the following examples. ##STR31##

In each of Schemes I and II, the substituents Y and W are as definedabove for formula I.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

One skilled in the art will recognize that modifications may be made inthe present invention without deviating from the spirit or scope of theinvention. The invention is illustrated further by the followingexamples which are not to be construed as limiting the invention orscope of the specific procedures or compositions described herein.

The starting materials may be obtained from commercial sources, preparedfrom commercially available organic compounds, or by using well knownsynthetic methods.

EXAMPLE I ##STR32##

A mixture of 2-bromo-2'-nitroacetophenone (18 g), 4-methoxybenzamidine(20 g), and silica gel (20 g) in acetonitrile (500 ml) is heated at 40°C. for 24 hours. The reaction is evaporated and the residue put on alayer of silica gel and eluted with 50% ethyl acetate/hexane (1500 ml).The solution is evaporated under reduced pressure to approximately 250ml and extracted with 5% HCl (3×250 ml) . The combined aqueous solutionis basified with K₂ CO₃ and extracted with ethyl acetate (3×400 ml) toafford 2-(4-methoxyphenyl)-4-(2-nitrophenyl)-imidazole (17 g) as a darkyellow oil which is used in the next step without further purification.

EXAMPLE II ##STR33##

2-(4-Methoxyphenyl)-4-(2-nitrophenyl)imidazole (10 g) is mixed with EtOH(80 ml) and 5% Pd-C (wet, 2 g). The mixture is shaken under hydrogen at50 psi for 45 min. then filtered through Celite. The filtrate isevaporated under reduced pressure to yield2-(4-methoxyphenyl)-4-(2-aminophenyl)imidazole (9.2 g) as a brown solidwhich is used in the next step without further purification.

EXAMPLE III ##STR34##

2-(4-Methoxyphenyl)-4-(2-aminophenyl)imidazole (5 g) is dissolved inacetic acid (20 ml) and formaldehyde (37% in water, 1.53 ml) is added.The reaction is stirred for 2 min., diluted with ethyl acetate (100 ml),and extracted with 5%HCl (250 ml). The aqueous layer is basified with K₂CO₃, then extracted with ethyl acetate. The organic layer is evaporatedunder reduced pressure and the residue is recrystallized fromdichloromethane to afford 3-(4-methoxyphenyl)-5,6-dihydroimidazo1,5-c!quinazoline (3 g) as a light brown solid. m.p. 190°-191° C.

EXAMPLE IV ##STR35##

To a mixture of 3-(4-methoxyphenyl)-5,6-dihydroimidazo 1,5-c!quinazoline(100 mg) and diisopropylethylamine (50 ml) in THF (20 ml) is addedphosgene (20% in Toluene, 100 ml) and the mixture stirred at RT for 1.5hours. The reaction is evaporated to dryness and piperidine (100 ml) inTHF (20 ml) is added to the reaction vessel. The reaction is stirred for3 min., then extracted with ethyl acetate (200 ml). The organic layer isevaporated and the residue is purified by preparative-platechromatography (75% ethyl acetate/hexane) to afford3-(4-methoxyphenyl)-5,6-dihydro-6- (1-piperidino)carbonyl!imidazo1,5-c!quinazoline (Compound 1) as an oil. The free base is dissolved inether, and saturated HCl-ethyl acetate solution is added to give thehydrochloride salt. m.p. 168°-170° C.

EXAMPLE V

The following compounds are prepared essentially according to theprocedures described in Example IV:

a) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(N,N-dimethyl-amino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 2).

b) 3-(4-Methoxyphenyl)-5,6-dihydro-6- (1-morpholino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 3). m.p. 208°-211° C.

c) 3-(4-Methoxyphenyl)-5,6-dihydro-6- (N,N-diethylamino-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 4).

d) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(N,N-dipropyl-amino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 5).

e) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(N,N-dibutyl-amino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 6).

f) 3-(4-Methoxyphenyl)-5,6-dihydro-6- (N-ethylamino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 7).

g) 3-(4-Methoxyphenyl)-5,6-dihydro-6- (1-pyrrolidino) carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 8).

h) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(1-hexamethylene-imino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride(Compound 9). m.p. 173°-175° C.

i) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(1-heptamethyl-eneimino)carbonyl!-imidazo 1,5-c!quinazolinehydrochloride (Compound 10). m.p. 197°-199° C.

j) 3-(4-Methoxyphenyl)-5,6-dihydro-6- (1-piperazino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 11).

k) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(1-homopiperazino-carbonyl)imidazo1,5-c!quinazoline hydrochloride (Compound 12).

l) 3-(4-Methoxyphenyl)-5,6-dihydro-6-1-(2,5-dimethyl-piperazino)carbonyl!imidazo 1,5-c!quinazolinehydrochloride (Compound 13).

m) 3-(4-Methoxyphenyl)-5,6-dihydro-6-1-(3,5-dimethyl-piperazino)carbonyl!imidazo 1,5-c!quinazolinehydrochloride (Compound 14). m.p. >260° C.

n) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-methyl-piperazino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 15). m.p. >240° C.

o) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (1-piperidino)-carbonyl!imidazo1,5-!quinazoline hydrochloride (Compound 16).

p) 3-(3-Methoxyphenyl)-5,6-dihydro-6-(1-hexamethylene-imino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 17).

q) 3-Phenyl-5,6-dihydro-6- (1-hexamethyleneimino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 18).

r) 3-(2-Fluorophenyl)-5,6-dihydro-6- (N-ethylamino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 19).

s) 3-(2-Fluorophenyl)-5,6-dihydro-6- (N-isopropyl)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 20).

t) 3-(2-Fluoro-4-methoxyphenyl)-5,6-dihydro-6-(1-hexa-methyleneimino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 21). m.p. 199°-202° C.

u) 3-(2-Fluoro-4-methoxyphenyl)-5,6-dihydro-6-(N-ethyl-amino)carbonyl!irnidazo 1,5-c!quinazoline hydrochloride(Compound 22).

v) 3-(2-Thiophene)-5,6-dihydro-6-(1-hexamethylene-imino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 23).

w) 3-(3-Thiophene)-5,6-dihydro-6- (1-piperidino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 24) m.p. 56°-64° C.

x) 3-(3-Thiophene)-5,6-dihydro-6-(1-hexamethylene-imino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 25).

y) 3-(3-Thiophene)-5,6-dihydro-6- (1-pyrrolidino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 26). z)3-(3-Thiophene)-5,6-dihydro-6- (1-morpholino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 27).

aa) 3-(4-Pyridyl)-5,6-dihydro-6- (1-hexamethyleneimino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 28).

bb) 3-(4-Pyridyl)-5,6-dihydro-6- (1-morpholino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 29).

cc) 3-(4-Methylphenyl)-5,6-dihydro-6-(1-hexamethylene-imino)carbonyl!imidazo1,5-c!quinazoline hydrochloride(Compound 30).

dd) 3-(4-Methylphenyl)-5,6-dihydro-6- (3-pyridyl)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 31).

ee) 3-(3-Methoxyphenyl)-5,6-dihydro-6-(1-hexamethyl-eneimino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 32).

ff) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (1-morpholino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 33).

gg) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (1-pyrrolidino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 34).

hh) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (1-piperidino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 35).

ii) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (3-pyridyl)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 36).

jj) 3-(3-Methoxyphenyl)-5,6-dihydro-6- phenylcarbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 37).

kk) 3-(3-Methoxyphenyl)-5,6-dihydro-6- (3-fluorophenyl)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 38).

ll) 3-(3-Methoxyphenyl)-5,6-dihydro-6-(N,N-dimethyl-amino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 39).

mm) 3-(3-Methoxyphenyl)-5,6-dihydro-6-(N,N-diethyl-amino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride(Compound 40).

nn) 3-Phenyl-5,6-dihydro-6- (N,N-diethylamino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 41).

oo) 3-Phenyl-5,6-dihydro-6- (1-pyrrolidino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 42).

pp) 3-Phenyl-5,6-dihydro-6- (1-piperidino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 43).

qq) 3-Phenyl-5,6-dihydro-6- (1-morpholino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 44).

rr) 3-Phenyl-5,6-dihydro-6- (1-heptamethyleneimino)-carbonyl!imidazo1,5-c!quinazoline hydrochloride (Compound 45). m.p. 230°-233° C.

ss) 3-Phenyl-5,6-dihydro-6- cyclopropylcarbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 46).

tt) 3-Phenyl-5,6-dihydro-6- cyclohexylcarbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 47).

uu) 3-Phenyl-5,6-dihydro-6- (2-thiophene)carbonyl!-imidazo1,5-c!quinazoline hydrochloride (Compound 48).

EXAMPLE VI ##STR36##

To a mixture of 3-(4-methoxyphenyl)-5,6-dihydroimidazo 1,5-c!quinazoline(100 mg) and diisopropylethylamine (50 ml) in THF (20 ml) is addedacetyl chloride (50 ml) and the mixture stirred at RT for 5 hours. Thereaction is extracted with ethyl acetate (200 ml), the solventevaporated, and the residue is purified by preparative-platechromatography (75% ethyl acetate/hexane) to afford3-(4-methoxyphenyl)-5,6-dihydro-6-acetylimidazo 1,5-c!-quinazoline(Compound 49) as a light yellow solid. m.p. 80°-82° C.

EXAMPLE VII ##STR37##

Phosgene (20% in Toluene, 150 ml) is added slowly to a mixture of2-(4-methoxyphenyl)-4-(2-aminophenyl) imidazole (250 mg) anddiisopropylethylamine (100 ml) in THF (25 ml). The reaction is allowedto stir at RT for 5 min., then extracted with ethyl acetate (300 ml).The organic layer is evaporated and the residue is recrystallized fromethanol to afford 3-(4-methoxyphenyl)-5,6-dihydro-5-oxo- 6H!imidazo1,5-c!-quinazoline (Compound 50) as a white solid, m.p. 267°-268° C.

EXAMPLE VIII ##STR38##

To 3-(4-methoxyphenyl)-5,6-dihydro-5-oxo- 6H!-imidazo1,5-c!quinazoline(100 mg) dissolved in DMF (5 ml) is added potassiumt-butoxide (1M in THF, 250 ml). After stilling for 30 min, iodoethane(100ml) is added, and the mixture is allowed to stand at roomtemperature for 24 hours. The reaction is extracted with ethyl acetateand the organic layer evaporated under reduced pressure to approximately3 ml. Saturated HCI-ethyl acetate solution is added, and the precipitatefiltered to afford 3-(4-methoxy-phenyl)-5,6-dihydro-5-oxo-6-ethylimidazo1,5-c!quinazoline hydrochloride as a yellow solid (Compound 51).m.p. >170° C.

EXAMPLE IX

The following compounds are prepared essentially according to theprocedures described in Examples VI-VIII:

a) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(1-propionyl)-imidazo1,5-c!quinazoline(Compound 52). m.p. 165°-167° C.

b) 3-(4-Methoxyphenyl)-5,6-dihydro-6-benzoylimidazo- 1,5-c!quinazoline(Compound 53).

c) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-chlorobenzoyl)-imidazo1,5-c!quinazoline hydrochloride (Compound 54).

d) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-methoxy-benzoyl)imidazo1,5-c!quinazoline hydrochloride (Compound 55).

e) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-fluorobenzoyl)-imidazo1,5-c!quinazoline hydrochloride (Compound 56). m.p. 251°-254° C.

f) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3-fluorobenzoyl)-imidazo1,5-c!quinazoline (Compound 57).

g) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2-fluorobenzoyl)-imidazo1,5-c!quinazoline (Compound 58).

h) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-methylbenzoyl)-imidazo1,5-c!quinazoline (Compound 59).

i) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3-methylbenzoyl)-imidazo1,5-c!quinazoline (Compound 60).

j) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2-methylbenzoyl)-imidazo1,5-c!quinazoline (Compound 61).

k) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(4-ethylbenzoyl)-imidazo1,5-c!quinazoline (Compound 62).

l) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3-fluoro-2-methylbenzoyl)imidazo1,5-c!quinazoline (Compound 63).

m) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3-fluoro-4-methylbenzoyl)imidazo1,5-c!quinazoline (Compound 64).

n) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2,3-dimethyl-benzoyl)imidazo1,5-c!quinazoline (Compound 65).

o) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2,4-dimethyl-benzoyl)imidazo1,5-c!quinazoline (Compound 66).

p) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2,5-dimethyl-benzoyl)imidazo1,5-c!quinazoline (Compound 67).

q) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3,4-dimethyl-benzoyl)imidazo1,5-c!quinazoline (Compound 68).

r) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3,5-dimethyl-benzoyl)imidazo1,5-c!quinazoline (Compound 69).

s) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(2-methoxy-benzoyl)imidazo1,5-c!quinazoline (Compound 70).

t) 3-(4-Methoxyphenyl)-5,6-dihydro-6-(3-methoxy-benzoyl)imidazo1,5-c!quinazoline (Compound 71).

u) 3-(2-Fluoro-4-methoxyphenyl)-5,6-dihydro-6-benzoyl-imidazo1,5-c!quinazoline (Compound 72). m.p. 196°-197° C.

v) 3-(2-Fluoro-4-methoxyphenyl)-5,6-dihydro-6-acetyl-imidazo1,5-c!quinazoline hydrochloride (Compound 73). m.p. 113°-116C.

w) 3-(2-Fluorophenyl)-5,6-dihydro-5-oxo- 6H!imidazo 1,5-c!quinazoline.(Compound 74).

x) 3-Phenyl-5,6-dihydro-5-oxo- 6H!imidazo 1,5-c!-quinazoline (Compound75). m.p. 280°-283° C.

y) 3-(2-Fluorophenyl)-5,6-dihydro-5-oxo-6-ethyl-imidazo1,5-c!quinazoline (Compound 76).

z) 3-(2-Fluorophenyl)-5,6-dihydro-5-oxo-6-isopropyl-imidazo1,5-c!quinazoline (Compound 77).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula I!: ##STR39## or thepharmaceutically acceptable nontoxic salts thereof wherein: X is oxygen,H₂ or sulfur;Y is hydrogen, alkyl, alkenyl, (substituted)arylalkyl,alkoxycarbonyl, acyl, aroyl, alkoxyalkyl, alkoxy, alkylamino-carbonyl,cycloalkylaminocarbonyl, aryl or heteroaryl each of which is optionallysubstituted with halogen, lower alkyl, amino lower alkyl, or loweralkoxy; W is alkyl, arylalkyl or heteroarylalkyl, where each aryl groupis optionally substituted with up to two groups independently selectedfrom halogen, alkyl, alkoxy, trifluoromethyl, lower alkyl, amino loweralkyl, mono- or dialkyl amino where each alkyl is independently loweralkyl; or W is aryl or heteroaryl, each of which is optionallysubstituted with up to two groups independently selected from halogen,hydroxy, lower alkyl, or lower alkoxy having 1-6 carbon atoms; amino,mono- or dialkylamino where each alkyl is independently lower alkyl, andZ₁, Z₂, Z₃, and Z₄ independently represent nitrogen or C-R₁ where R₁ ishydrogen, halogen, hydroxy, amino, or phenyl or pyridyl optionally mono-or independently disubstituted with halogen, hydroxy, lower alkyl, orlower alkoxy.
 2. A compound of the formula: ##STR40## or apharmaceutically acceptable salt thereof wherein Y is hydrogen, alkyl,alkenyl, (substituted)arylalkyl, alkoxy, alkoxyalkyl, or aryl orheteroaryl each of which is optionally substituted with halogen, loweralkyl, amino lower alkyl, or lower alkoxy; orY is a group of theformula: ##STR41## where R_(c) represents alkoxy, lower alkyl, aryl,heteroaryl, mono- or dialkylamino, cycloalkylamino; and W is alkyl,arylalkyl or heteroarylalkyl, where each aryl group is optionallysubstituted with up to two groups independently selected from halogen,alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl, mono- ordialkyl amino where each alkyl is independently lower alkyl; or W isaryl or heteroaryl, each of which is optionally substituted with up totwo groups independently selected from halogen, hydroxy, lower alkyl, orlower alkoxy having 1-6 carbon atoms; amino, mono- or dialkylamino whereeach alkyl is independently lower alkyl.
 3. A compound of the formula:##STR42## or a pharmaceutically acceptable salt thereof wherein Y ishydrogen, alkyl, alkenyl, (substituted)arylalkyl, alkoxy, alkoxyalkyl,or aryl or heteroaryl each of which is optionally substituted withhalogen, lower alkyl, amino lower alkyl, or lower alkoxy; orY is a groupof the formula: ##STR43## where R_(c) represents alkoxy, lower alkyl,aryl, heteroaryl, mono- or dialkylamino, cycloalkylamino; and W isalkyl, arylalkyl or heteroarylalkyl, where each aryl group is optionallysubstituted with up to two groups independently selected from halogen,alkyl, alkoxy, trifluoromethyl, lower alkyl, amino lower alkyl, mono- ordialkyl amino where each alkyl is independently lower alkyl; or W isaryl or heteroaryl, each of which is optionally substituted with up totwo groups independently selected from halogen, hydroxy, lower alkyl, orlower alkoxy having 1-6 carbon atoms; amino, mono- or dialkylamino whereeach alkyl is independently lower alkyl.
 4. A compound according toclaim 1, which is 3-(4-methoxy-phenyl)-5,6-dihydro-6-(1-piperidino)carbonyl!imidazo 1,5-c!-quinazoline hydrochloride.
 5. Acompound according to claim 1, which is3-(4-methoxy-phenyl)-5,6-dihydro-6- (N,N-dimethylamino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride.
 6. A compound according to claim 1,which is 3-(4-methoxy-phenyl)-5,6-dihydro-6-(1-morpholino)-carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 7. Acompound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6- (N,N-diethylamino-carbonyl!-imidazo1,5-c!quinazoline hydrochloride.
 8. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(N,N-dipropylamino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride. 9.A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6- (N,N-dibutylamino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride.
 10. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(N-ethylamino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 11. Acompound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6- (1-pyrrolidino)carbonyl!imidazo1,5-c!quinazoline hydrochloride.
 12. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride.13. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(1-heptamethyleneimino)carbonyl!-irnidazo 1,5-c!quinazolinehydrochloride.
 14. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6- (1-piperazino)carbonyl!imidazo1,5-c!quinazoline hydrochloride.
 15. A compound according to claim 1,which is3-(4-methoxyphenyl)-5,6-dihydro-6-(1-homopiperazinocarbonyl)-imidazo1,5-c!quinazoline hydrochloride.
 16. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-1-(2,5-dimethylpiperazino)carbonyl!-imidazo 1,5-c!quinazolinehydrochloride.
 17. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-1-(3,5-dimethylpiperazino)carbonyl!-imidazo 1,5-c!quinazolinehydrochloride.
 18. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6- (4-methylpiperazino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride.
 19. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-(1-piperidino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 20. Acompound according to claim 1, which is3-(3-methoxyphenyl)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride.21. A compound according to claim 1, which is 3-phenyl-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!imidazo 1,5-c!-quinazoline hydrochloride.22. A compound according to claim 1, which is3-(2-fluorophenyl)-5,6-dihydro-6- (N-ethylamino)carbonyl!imidazo1,5-c!-quinazoline hydrochloride.
 23. A compound according to claim 1,which is 3-(2-fluorophenyl)-5,6-dihydro-6- (N-isopropyl)carbonyl!imidazo1,5-c!-quinazoline hydrochloride.
 24. A compound according to claim 1,which is 3-(2-fluoro-4-methoxyphenyl)-5,6-dihydro-6-(1-hexamethyleneimino)-carbonyl!imidazo 1,5-c!quinazoline hydrochloride.25. A compound according to claim 1, which is3-(2-fluoro-4-methoxyphenyl)-5,6-dihydro-6-(N-ethylamino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride.
 26. Acompound according to claim 1, which is 3-(2-thiophene)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.27. A compound according to claim 1, which is3-(3-thiophene)-5,6-dihydro-6- (1-piperidino)carbonyl!imidazo1,5-c!quinazoline hydrochloride.
 28. A compound according to claim 1,which is 3-(3-thiophene)-5,6-dihydro-6- (1-hexamethyleneimino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride. 29.A compound according to claim 1, which is 3-(3-thiophene)-5,6-dihydro-6-(1-pyrrolidino)carbonyl!imidazo 1,5-c!-quinazoline hydrochloride.
 30. Acompound according to claim 1, which is 3-(3-thiophene)-5,6-dihydro-6-(1-morpholinocarbonyl!imidazo 1,5-c!-quinazoline hydrochloride.
 31. Acompound according to claim 1, which is 3-(4-pyridyl)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!imidazo 1,5-c!-quinazoline hydrochloride.32. A compound according to claim 1, which is3-(4-pyridyl)-5,6-dihydro-6- (1-morpholino)carbonyl!imidazo1,5-c!quinazoline hydrochloride.
 33. A compound according to claim 1,which is 3-(4-methylphenyl)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride.34. A compound according to claim 1, which is3-(4-methylphenyl)-5,6-dihydro-6- (3-pyridyl)carbonyl!imidazo1,5-c!-quinazoline hydrochloride.
 35. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-(1-hexamethyleneimino)carbonyl!-imidazo 1,5-c!quinazoline hydrochloride.36. A compound according to claim 1, which is3-(3-metoxy-phenyl)-5,6-dihydro-6- (1-morpholino)carbonyl!imidazo1,5-c!quinazoline hydrochloride.
 37. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-(1-pyrrolidino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 38. Acompound according to claim 1, which is3-(3-methoxyphenyl)-5,6-dihydro-6- (1-piperidino)carbonyl!imidazo1,5-c!-quinazoline hydrochloride.
 39. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6- (3-pyridyl)carbonyl!imidazo1,5-c!-quinazoline hydrochloride.
 40. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-benzoyl-imidazo1,5-c!-quinazoline hydrochloride.
 41. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-(3-fluorophenyl)carbonyl!imidazo- 1,5-c!quinazoline hydrochloride.
 42. Acompound according to claim 1, which is3-(3-methoxyphenyl)-5,6-dihydro-6- (N,N-dimethylamino)carbonyl!-imidazo1,5-c!quinazoline hydrochloride.
 43. A compound according to claim 1,which is 3-(3-methoxyphenyl)-5,6-dihydro-6-(N,N-diethylamino)carbonyl!imidazo- 1,5-c!quinazoline hydrochloride. 44.A compound according to claim 1, which is 3-phenyl-5,6-dihydro-6-(N,N-diethylamino)carbonyl!imidazo 1,5-c!-quinazoline hydrochloride. 45.A compound according to claim 1, which is 3-phenyl-5,6-dihydro-6-(1-pyrrolidino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 46. Acompound according to claim 1, which is 3-phenyl-5,6-dihydro-6-(1-piperidino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 47. Acompound according to claim 1, which is 3-phenyl-5,6-dihydro-6-(1-morpholino)carbonyl!imidazo 1,5-c!quinazoline hydrochloride.
 48. Acompound according to claim 1, which is3-phenyl-5,6-dihydro-6-imidazo-quinazoline hydrochloride.
 49. A compoundaccording to claim 1, which is 3-phenyl-5,6-dihydro-6-imidazoquinazoline hydrochloride.
 50. A compound according to claim 1, which is3-phenyl-5,6-dihydro-6- cyclohexylcarbonyl!imidazo 1,5-c!quinazolinehydrochloride.
 51. A compound according to claim 1, which is3-phenyl-5,6-dihydro-6- (2-thiophene)carbonyl!imidazo 1,5-c!quinazolinehydrochloride.
 52. A compound according to claim 1, which is3-(4-methoxy-phenyl)-5,6-dihydro-6-acetylimidazo 1,5-c!quinazoline. 53.A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-5-oxo- 6H!imidazo 1,5-c!quinazoline. 54.A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-5-oxo-6-ethylimidazo 1,5-c!quinazolinehydrochloride.
 55. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(1-propionyl)imidazo1,5-c!quinazoline.
 56. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-benzoylimidazo 1,5-c!quinazoline. 57.A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(4-chlorobenzoyl)imidazo1,5-c!-quinazoline hydrochloride.
 58. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(4-methoxybenzoyl)imidazo1,5-c!-quinazoline hydrochloride.
 59. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(4-fluorobenzoyl)imidazo1,5-c!-quinazoline hydrochloride.
 60. A compound according to claim 1,which is 3-(4-methoxyphenyl)-5,6-dihydro-6-(3-fluorobenzoyl)imidazo1,5-c!-quinazoline.
 61. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2-fluorobenzoyl)imidazo-quinazoline.62. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(4-methylbenzoyl)imidazo1,5-c!-quinazoline.
 63. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(3-methylbenzoyl)imidazo1,5-c!-quinazoline.
 64. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2-methylbenzoyl)imidazo1,5-c!-quinazoline.
 65. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(4-ethylbenzoyl)imidazo1,5-c!-quinazoline.
 66. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(3-fluoro-2-methylbenzoyl)imidazo-1,5-c!-quinazoline.
 67. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(3-fluoro-4-methylbenzoyl)imidazo-1,5-c!quinazoline.
 68. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2,3-dimethylbenzoyl)imidazo1,5-c!-quinazoline.
 69. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2,4-dimethylbenzoyl)imidazo1,5-c!-quinazoline.
 70. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2,5-dimethylbenzoyl)imidazo1,5-c!-quinazoline.
 71. A compound according to claim 1, which is3-(4-methoxy-phenyl)-5,6-dihydro-6-(3,4-dimethylbenzoyl)imidazo1,5-c!-quinazoline.
 72. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(3,5-dimethylbenzoyl)imidazo1,5-c!-quinazoline.
 73. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(2-methoxybenzoyl)imidazo1,5-c!-quinazoline.
 74. A compound according to claim 1, which is3-(4-methoxyphenyl)-5,6-dihydro-6-(3-methoxybenzoyl)imidazo1,5-c!-quinazoline.
 75. A compound according to claim 1, which is3-(2-fluoro-4-methoxyphenyl)-5,6-dihydro-6-benzoylimidazo1,5-c!-quinazoline.
 76. A compound according to claim 1, which is3-(2-fluoro-4-methoxyphenyl)-5,6-dihydro-6-acetylimidazo1,5-c!-quinazoline hydrochloride.
 77. A compound according to claim 1,which is 3-(2-fluorophenyl)-5,6-dihydro-5-oxo- 6H!imidazo1,5-c!quinazoline.
 78. A compound according to claim 1, which is3-phenyl-5,6-dihydro-5-oxo- 6H!imidazo 1,5-c!quinazoline.
 79. A compoundaccording to claim 1, which is3-(2-fluorophenyl)-5,6-dihydro-5-oxo-6-ethylimidazo 1,5-c!quinazoline.80. A compound according to claim 1, which is3-(2-fluorophenyl)-5,6-dihydro-5-oxo-6-isopropylimidazo1,5-c!quinazoline.
 81. A compound according to claim 3, wherein Y isselected from the group consisting of ##STR44## where A is NH, CH₂ oroxygen; E is oxygen or nitrogen; and R' and R" independently representhydrogen, halogen, hydroxy or lower alkoxy.
 82. A compound according toclaim 3, wherein W represents 2- or 3- thienyl, phenyl, or 3- or4-alkoxyphenyl where the phenyl group is optionally halogenated.